Epigenetic Rewiring Connects Aging to Alzheimer’s Pathology in the Human Prefrontal Cortex

The epigenetic mechanisms that connect aging to neurodegeneration remain incompletely understood, particularly in non-European populations. To address this gap, we constructed a comprehensive DNA methylation atlas of the human prefrontal cortex (PFC) from 1,057 postmortem brain samples (ages 1-106) as part of the China Brain Multi-Omics Atlas Project (CBMAP). This represents the largest DNA methylation dataset of East Asian brain tissue to date and provides a critical resource for understanding aging and Alzheimer’s disease (AD) in underrepresented populations. We found that over one-third of CpG sites exhibit significant age-associated methylation changes, with high concordance between Asian and European ancestries, but marked divergence between brain and peripheral blood methylation profiles. In the PFC, age-related CpGs were enriched near histone genes and associated with transcriptomic signatures of neuronal decline. Importantly, we identified 485 CpGs linked to AD neuropathologic change (ADNC), including 228 novel loci enriched in immune regulation, vesicle trafficking, and extracellular matrix remodeling—hallmark pathways of AD. Mediation analysis revealed that DNA methylation accounts for 27.3% of aging’s effect on ADNC, highlighting a key mechanistic link. Notably, CpG site cg09221482 mediates the relationship between aging and neurofibrillary tangle severity via MAP3K4 expression. Together, these findings uncover novel aging-associated epigenetic signatures that contribute to AD pathology and establish DNA methylation as a critical intermediary bridging aging and neurodegeneration, particularly in East Asian populations.